Blocking NMDA receptors in the hippocampal dentate gyrus with AP5 produces analgesia in the formalin pain test.

The hippocampus is an integral component of the "limbic" system and, as such, may contribute to the negative affect and avoidance motivation experienced during pain. A substantial body of evidence indicates that the hippocampus processes pain-related information, that some hippocampal neurons respond exclusively to painful stimulation, and that long-term anatomical changes occur in dentate gyrus neurons, following noxious physical stimulation. NMDA receptor antagonist drugs administered to the hippocampus interfere with long-term potentiation, learning, and memory; these same drugs, when applied to the spinal cord, prevent the long-term neurophysiological changes caused by noxious physical stimulation. This experiment tested whether blocking NMDA receptors in the hippocampal formation reduces nociceptive behaviors in an animal model of persistent human pain. The competitive NMDA receptor antagonist AP5 was injected into the dentate gyrus of alert, unrestrained rats either 5 min before or 15 min following the administration of a subcutaneous injection of formalin irritant. Pain behaviors in both acute and tonic phases of the formalin test were significantly reduced by AP5 treatments. These results support the hypothesis that the hippocampal formation is involved in pain-related neural processing and that NMDA receptor-sensitive mechanisms in the hippocampus are involved in pain perception and/or the expression of pain-related behaviors.

Central neuroplasticity and pathological pain.

The traditional specificity theory of pain perception holds that pain involves a direct transmission system from somatic receptors to the brain. The amount of pain perceived, moreover, is assumed to be directly proportional to the extent of injury. Recent research, however, indicates far more complex mechanisms. Clinical and experimental evidence shows that noxious stimuli may sensitize central neural structures involved in pain perception. Salient clinical examples of these effects include amputees with pains in a phantom limb that are similar or identical to those felt in the limb before it was amputated, and patients after surgery who have benefited from preemptive analgesia which blocks the surgery-induced afferent barrage and/or its central consequences. Experimental evidence of these changes is illustrated by the development of sensitization, wind-up, or expansion of receptive fields of CNS neurons, as well as by the enhancement of flexion reflexes and the persistence of pain or hyperalgesia after inputs from injured tissues are blocked. It is clear from the material presented that the perception of pain does not simply involve a moment-to-moment analysis of afferent noxious input, but rather involves a dynamic process that is influenced by the effects of past experiences. Sensory stimuli act on neural systems that have been modified by past inputs, and the behavioral output is significantly influenced by the "memory" of these prior events. An increased understanding of the central changes induced by peripheral injury or noxious stimulation should lead to new and improved clinical treatment for the relief and prevention of pathological pain.

Pain and the neuromatrix in the brain.

The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network-the "body-self neuromatrix"-in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Acute pains evoked by brief noxious inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernible injury or pathology, remain a mystery. Furthermore, chronic psychological or physical stress is often associated with chronic pain, but the relationship is poorly understood. The neuromatrix theory of pain provides a new conceptual framework to examine these problems. It proposes that the output patterns of the body-self neuromatrix activate perceptual, homeostatic, and behavioral programs after injury, pathology, or chronic stress. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation, or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.

Age differences in nociception and pain behaviours in the rat.

Much remains to be learned about the effects of ageing on pain. Studies of life-span changes in nociception and pain behaviours in the rat are equivocal making it difficult to draw firm conclusions. This paper reviews the available data and finds that age differences in nociception may be dependent on the pain test employed. Specifically, reflexive responses to nociceptive stimuli do not change with age while there may be no change or a linear decrease with age on more highly organized tests of nociception. Interestingly, age differences in pain behaviours on models of tissue injury and inflammation may not be linear. It is shown that important changes that begin at mid-life in neuroanatomy, neurochemistry and endogenous pain inhibition may be associated with alterations in pain sensitivity. Several testable hypotheses which might encourage future research in this domain are developed throughout this paper.

Nausea and vomiting during pregnancy: A prospective study of its frequency, intensity, and patterns of change.

OBJECTIVE: Our purpose was to provide a detailed description of patterns of nausea and vomiting of pregnancy. STUDY DESIGN: A prospective study was performed with 160 women who provided daily recordings of frequency, duration, and severity of nausea and vomiting. RESULTS: Seventy-four percent of women reported nausea lasting a mean of 34.6 days. "Morning sickness" occurred in only 1.8% of women, whereas 80% reported nausea lasting all day. Only 50% of women were relieved by 14 weeks' gestation; 90% had relief by week 22. Data based on the McGill Nausea Questionnaire indicate that the nausea experienced by pregnant women is similar in character and intensity to the nausea experienced by patients undergoing cancer chemotherapy. CONCLUSIONS: Traditional teachings about nausea and vomiting of pregnancy are contradicted by our findings. Standardized tools for measuring the distribution, duration, and intensity of nausea are applicable to the study of nausea and vomiting of pregnancy and could be used in clinical trials to assess palliative measures.

Del umbral a la neuromatriz / From the gate to the neuromatrix

La contribución más importante de la teoría de la regulación del umbral a nuestro conocimiento del dolor fue su hincapié en los mecanismos neurales centrales. Esa teoría obligó a las ciencias médicas y biológicas a concebir el cerebro como un sistema activo que filtra, selecciona y modula los estímulos. Por otra parte, las astas dorsales dejaron de ser estaciones de transmisión meramente pasivas para convertirse en lugares donde ocurrían actividades dinámicas (inhibición, excitación y modulación). El gran reto que nos plantea el futuro es llegar a comprender el funcionamiento del cerebro. Por ello, he propuesto que el cerebro posee una red neural -en la neuromatriz de la conciencia corporal- que integra diferentes estímulos para producir el tipo de respuesta que provoca dolor. La neuromatriz de la conciencia corporal está formada por una red neural ampliamente distribuida y formada por componentes paralelos somatosensoriales, límbicos y talamocorticales que son responsables de las dimensiones senso-discriminativas, afectivo-motivacionales y evaluo-cognitivas de la experiencia del dolor. La arquitectura sináptica de la neuromatriz está determinada por factores genéticos y sensoriales. La respuesta "neuroespecífica" de la n e u romatriz -conjunto de impulsos nerviosos con distintas dimensiones temporales y espaciales- es producida por programas neurales genéticamente incorporados a la neuro matriz que determinan las cualidades específicas y otras propiedades de la experiencia y la conducta del dolor. Entre los diferentes estímulos que actúan sobre los programas de la neuromatriz y contribuyen a la respuesta neuroespecífica se encuentran (1) los estímulos sensoriales (receptores cutáneos, viscerales y otros receptores somáticos); (2) estímulos visuales y otros estímulos sensoriales que influyen en la interp retación cognitiva de la situación; (3) estímulos cognitivos y emocionales fásicos y tónicos desde otras áreas del cere b ro ; (4) modulación inhibidora neural intrínseca inherente en todas las funciones cerebrales; (5) la actividad de los sistemas de regulación del estrés del organismo, entre ellos las citoquinas y los sistemas endocrino, autonómico, inmune y opiáceo. Hemos recorrido un largo camino desde el concepto psicofísico que planteaba una relación simple y unívoca entre lesión y dolor. Ahora existe un marco teórico en donde el potente sistema de estrés y las funciones cognitivas del cerebro, además de los estímulos sensoriales tradicionales, modulan una plantilla genéticamente determinada para la conciencia corporal (AU)

Pain--an overview.

The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network--the "body-self neuromatrix"--in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Pains that are evoked by noxious sensory inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernible injury or pathology, remain a mystery. The neuromatrix theory of pain, however, provides a new conceptual framework that is consistent with recent clinical evidence. It proposes that the output patterns of the neuromatrix activate perceptual, homeostatic and behavioral programs after injury or pathology, or as a result of multiple other inputs that act on the neuromatrix. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix.

Measurement of pain.

Pain is a personal, subjective experience influenced by cultural learning, the meaning of the situation, attention, and other psychologic variables. Approaches to the measurement of pain include verbal and numeric self-rating scales, behavioral observation scales, and physiologic responses. The complex nature of the experience of pain suggests that measurements from these domains may not always show high concordance. Because pain is subjective, patients' self-reports provide the most valid measure of the experience. The VAS and the MPQ are probably the most frequently used self-rating instruments for the measurement of pain in clinical and research settings. The MPQ is designed to assess the multidimensional nature of pain experience and has been demonstrated to be a reliable, valid, and consistent measurement tool. A short-form MPQ is available for use in specific research settings when the time to obtain information from patients is limited and when more information than simply the intensity of pain is desired. The DDS was developed using sophisticated psychophysical techniques and was designed to measure separately the sensory and unpleasantness dimensions of pain. It has been shown to be a valid and reliable measurement of pain with ratio-scaling properties and has recently been used in a clinical setting. Behavioral approaches to the measurement of pain also provide valuable data. Further development and refinement of pain measurement techniques will lead to increasingly accurate tools with greater predictive powers.

A case of referred pain evoked by remote light touch after partial nerve injury.

An unusual case of referred pain is presented in which a 63-year-old man, who suffered a severe injury to his right hand and arm during young adulthood, describes the later development of dysesthesia and shooting pain in his arm subsequent to stimulation of the ipsilateral scalp, the temporal and infrazygomatic region of the face, and the back. Referred sensations of this type are usually reported following amputation of an arm. Clinical examination of the sensory and motor function of the arm and hand revealed partial damage to the radial, ulnar and median nerves as well as possible brachial plexus involvement. Interestingly, pain could be evoked by repeated light touches applied to the remote trigger areas suggesting the involvement of a 'wind-up'-like process.

Pain: an overview.

Until the 1960s, pain was considered an inevitable sensory response to tissue damage. There was little room for the affective dimension of this ubiquitous experience, and none whatsoever for the effects of genetic differences, past experience, anxiety, or expectation. In recent years, great advances have been made in our understanding of the mechanisms that underlie pain and in the treatment of people who complain of pain. The roles of factors outside the patient's body have also been clarified. Pain is probably the most common symptomatic reason to seek medical consultation. All of us have headaches, burns, cuts, and other pains at some time during childhood and adult life. Individuals who undergo surgery are almost certain to have postoperative pain. Ageing is also associated with an increased likelihood of chronic pain. Health-care expenditures for chronic pain are enormous, rivalled only by the costs of wage replacement and welfare programmes for those who do not work because of pain. Despite improved knowledge of underlying mechanisms and better treatments, many people who have chronic pain receive inadequate care.

Long-term patterns of morphine dosage and pain intensity among cancer patients.

Cancer pain remains a worldwide problem and some patients continue to be undermedicated because of concerns about tolerance and drug dependence. The aim of this study was to document the morphine intake of patients with chronic cancer pain in an inpatient palliative care unit and to describe the long-term pattern of morphine use and pain intensity in this patient population. With IRB approval and written informed consent, patients admitted over a 64-week period to the palliative care unit at the Royal Victoria Hospital, Montreal, were candidates for this study. Cancer patients receiving morphine for 30 days or longer who were able to complete the pain scale were included. Excluded were patients with a confused or clouded sensorium. Daily pain intensity was recorded by the PPI (0-5 scale) of the McGill pain questionnaire. The daily morphine consumption was recorded and the occurrence and intensity of breakthrough pain were also recorded. Of the 35 potential candidates for study, 17 patients with a mean age of 59 (14) years completed the study. Patients were followed up for a mean of 82 (52) days. The mean (S.D.) daily morphine dosage at study entry was 135 (127) mg, and the daily morphine dose at study completion was 244 (240) mg. There was no evidence that any patient rapidly developed tolerance to morphine. Pain was well controlled for most patients. For 10 of 17 patients, 93% reported PPI scores of either 0 or 1. Occasional breakthrough pain was experienced by 4 of these 10 patients. Four other patients reported 79% of their PPI scores as either 0 or 1, and 18% of the PPI scores as either 2 (discomforting) or 3 (disturbing), Thus 82% of patients had good to excellent pain control. Three of 17 patients spent more than four months in the unit and had less than good pain control. All of these patients had neuropathic cancer pain. These results support the conclusion that pain was well controlled for most cancer patients, and that increases in daily morphine dose, when it occurred, generally developed over a period of weeks to months, and a pattern of rapid escalation in morphine dose did not occur.

Age differences in the response to the formalin test in rats.

We report the results of a study designed to assess age differences in the response to the formalin test, a model of tissue injury and inflammation, while controlling for differences in weight and motoric abilities in three groups of adult male Long-Evans rats: young (3 months old), middle-aged (18 months old), and old (24 months old). The first part of the study assessed initial differences in responsivity and found that the middle-aged group showed the greatest response, whereas the young and old groups did not differ from each other. In the second part of the study, the young and middle-aged animals were followed for a 4-month period. The formalin test was repeated at 2-month intervals. These results indicate that there may be an age-associated change in the sensitivity to tonic pain and that this sensitivity may peak at mid-life.

Psychostimulant drugs potentiate morphine analgesia in the formalin test.

Recent research has shown that the psychostimulant drug dextroamphetamine can increase the analgesia produced by opioids. Despite the strong, positive results in human clinical subjects and in animals, this combination is rarely used in clinical practice. The purpose of this paper is to investigate whether the psychostimulant drug methylphenidate (MP) can potentiate morphine analgesia in the rat formalin test, and to compare its effectiveness to that of dextroamphetamine (AMP). The formalin test was used because its long-lasting pain of moderate intensity resembles human clinical pain. Two different drug administration times were used to observe whether the early phase of the formalin response would be differentially affected by the drugs. At Drug Administration Time 1, rats received morphine 30 min prior to the formalin injection (-30 min) and MP or AMP 20 min prior to the formalin injection (-20 min). At Drug Administration Time 2, rats received morphine 10 min prior to the formalin injection (-10 min) and MP or AMP immediately prior to the formalin injection (0 min). All drugs were given subcutaneously. The results indicate that low doses of MP or AMP potentiate the analgesic effects of morphine. The clinical value of these drug combinations merits further investigation in animals and in humans.

Potentiation of opioid analgesia by psychostimulant drugs: a review.

Recent research has investigated drug combinations that enhance the analgesic effectiveness of their component substances. Many studies have examined the combination of opioids and psychostimulant drugs, such as amphetamine and methylphenidate. Despite the positive results reported in the literature, this combination is rarely used in clinical practice. The purpose of this paper is to review the literature on the opioid-amphetamine combination. Experiments with animal and human subjects provide convincing evidence that d-amphetamine or methylphenidate potentiate the analgesic effects of morphine. Psychostimulant drugs have been shown in animal studies to possess intrinsic analgesic properties and to have the ability to enhance the analgesic properties of opioids when both types of drugs are given in combination. Studies with human subjects have confirmed the enhancement of opioid analgesia by amphetamines and, in addition, have demonstrated that psychostimulant drugs produce a decrease in somnolence and an increase in general cognitive abilities. The greater cognitive alertness, moreover, allows the use of larger opioid doses, which can produce a substantial increase in analgesia. These results indicate another possible method to enhance the quality of life in patients with difficult pain problems. Although the enhanced cognitive effects are well established, the effects on pain need further study to determine the mechanisms of action and the drug combinations and administration patterns that would maximize their effects.

Phantom limbs in people with congenital limb deficiency or amputation in early childhood.

It is widely believed that people who are congenitally limb-deficient or suffer a limb amputation at an early age do not experience phantom limbs. The present study reports on a sample of 125 people with missing limbs and documents phantom experiences in 41 individuals who were either born limb-deficient (n = 15) or underwent amputation before the age of 6 years (n = 26). These cases provide evidence that phantom limbs are experienced by at least 20% of congenitally limb-deficient subjects and by 50% of subjects who underwent amputations before the age of 6 years. The phantoms are detailed and can be described in terms of size, shape, position, movement and temporal properties. The perceptual qualities of the phantoms can also be described by sensory descriptors and are reported as painful by 20% of subjects with phantoms in the congenital limb deficient group and 42% of young amputees. It is argued that these phantom experiences provide evidence of a distributed neural representation of the body that is in part genetically determined.

Repeated cold water swim produces delayed nociceptive responses, but not analgesia, for tonic pain in the rat.

Earlier studies have demonstrated that cold water swim (CWS) produces stress-induced analgesia in tests of brief, phasic pain and produces a delayed nociceptive response (DNR) for more prolonged tonic pain. The present study reports the effect of repeated CWS on tonic pain, as measured by the formalin test. One group of rats was exposed to a 3.5-min swim in 2 degrees C water immediately prior to the formalin injection, to a 1.5-min swim at 50 min, and to another 1.5-min swim at 100 min postformalin injection. Compared to the no-swim control group, subjects which received repeated CWS had dramatically altered formalin pain responses. Formalin responses began just over 3 h postformalin injection, peaked at 4 h, and were still present at 5 h. Inspection of individual responses revealed a substantial degree of variability in the onset of responses, although the magnitude and duration of the formalin pain response remained at the same levels as those of control subjects. The lack of a decrease in the magnitude and duration of the delayed formalin responses indicates that repeated CWS does not produce analgesia for tonic pain. The period of stress, therefore, produces pain suppression but not loss of the mechanisms that subsequently underlie the pain. Earlier controls have ruled out peripheral mechanisms (such as retention of the formalin in the paw tissue). Rather, a memory mechanism appears to have been indicated and it is not lost, but persists until it can be manifested. Further research is needed to study the mechanisms responsible for the DNR.

Chronic pain in elderly people.

Chronic pain in elderly people has only recently begun to receive serious empirical consideration. There is compelling evidence that a significant majority of the elderly experience pain which may interfere with normal functioning. Nonetheless, a significant proportion of these individuals do not receive adequate pain management. Three significant factors which may contribute to this are (1) lack of proper pain assessment; (2) potential risks of pharmacotherapy in the elderly; and (3) misconceptions regarding both the efficacy of nonpharmacological pain management strategies and the attitudes of the elderly towards such treatments. In this review the most commonly used assessment instruments and patterns of age differences in the experience of chronic pain are described and evidence for the efficacy of psychological pain management strategies for this group is reviewed.

Electrical stimulation of the cingulum bundle and surrounding cortical tissue reduces formalin-test pain in the rat.

Surgical lesions of the cingulum bundle in humans produce marked decreases in severe pain associated with cancer, reflex sympathetic dystrophy and other forms of chronic pain. Similarly, a temporary block of the anterior cingulum bundle in the rat by microinjection of lidocaine produces significant decreases in formalin-pain and reduces autotomy following peripheral neurectomy. The present study explored the effect of electrical stimulation of the cingulum bundle/surrounding cortical tissue (CB/CT) on tonic pain in the rat. Experiment 1 examined changes in formalin-induced pain responses following a 2.5-min period (30 s/min for 5 min) of electrical stimulation of the CB/CT 15 min prior to the formalin injection. The stimulation produced a significant reduction of first-period and second-period pain responses. Experiment 2 examined changes in formalin-induced pain responses following a 2.5-min period (30 s/min for 5 min) of electrical stimulation of the CB/CT 20 min following the formalin injection. The stimulation produced a dramatic reduction in second-period pain responses which persisted for the duration of the 35-min post-stimulation test period. The fact that either electrical stimulation or surgical section of the CB/CT produces pain relief suggests that this region serves a complex role in pain processing. Since the cingulum bundle has major connections with all other structures of the limbic system, it is possible that electrical stimulation disrupts patterned activity in the system, which is known to play an especially important role in the affective-motivational dimension of pain.